a single-arm, multicenter exploratory clinical trial of anlotinib combined with tqb2450 and the sox regimen as first-line treatment for advanced gastric cancer with low pd-l1 expression

Conditions: Advanced Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma

Summary: to evaluate the efficacy and safety of anlotinib combined with tqb2450 and the sox regimen as first-line treatment for advanced gastric cancer with low pd-l1 expression

evaluation of the efficacy and safety of anlotinib in combination with tqb2450 and the sox regimen as first-line treatment for advanced gastric cancer with low pd-l1 expression. additionally, real-world data were collected from hospital-based patients receiving immune checkpoint inhibitor (ici)-combined chemotherapy as first-line therapy for pd-l1-low advanced gastric cancer to establish an external control cohort. the efficacy outcomes between the two treatment strategies were then compared.

Eligibility criteria:
inclusion criteria: * 1. willing and able to provide written informed consent and comply with study procedures. * 2. histologically or cytologically confirmed her2-negative (or her2 status undetermined) unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (including signet ring cell carcinoma, mucinous adenocarcinoma, and hepatoid adenocarcinoma variants). * 3. disease recurrence \>6 months after completion of (neo)adjuvant chemotherapy or radiotherapy. * 4. at least one measurable or evaluable lesion according to recist v1.1 criteria. measurable lesions must not have received prior local therapy (e.g., radiotherapy); however, lesions within previously irradiated fields may be designated as target lesions if documented progression is demonstrated per recist v1.1. * 5. age 18-75 years. * 6. ecog performance status 0-1. * 7. life expectancy ≥3 months. * 8. organ function requirements and laboratory test criteria during screening (1) complete blood count (cbc) criteria： hemoglobin (hb): ≥ 90 g/l (no blood transfusion within 14 days) absolute neutrophil count (anc): ≥ 1.5 × 10⁹/l platelet count (plt): ≥ 100 × 10⁹/l (no use of interleukin-11 \[il-11\] or thrombopoietin \[tpo\] within 14 days) white blood cell count (wbc): ≥ 4.0 × 10⁹/l (no granulocyte colony-stimulating factor \[g-csf\] administration within 14 days) (2) biochemical panel requirements: total bilirubin (tbil): ≤ 1.5 × uln (upper limit of normal),alanine aminotransferase (alt) \& aspartate aminotransferase (ast): ≤ 2.5 × uln,serum creatinine (cr): ≤ 1.5 × uln or creatinine clearance (crcl): ≥ 60 ml/min (calculated by cockcroft-gault formula),serum albumin: ≥ 25 g/l (2.5 g/dl) for subjects with hepatic metastases:aspartate aminotransferase (ast) and alanine aminotransferase (alt): ≤ 5 × uln，white blood cell count (wbc): ≥ 4 × 10⁹/l，platelet count (plt): ≥ 100 × 10⁹/l (without transfusion support)， absolute neutrophil count (anc): ≥ 1.5 × 10⁹/l (without granulocyte colony-stimulating factor \[g-csf\] therapy) (3) cardiac function assessment (echocardiography)：left ventricular ejection fraction (lvef): ≥ 50% (or above institutional lower limit of normal) (4) coagulation profile：international normalized ratio (inr) or prothrombin time (pt): ≤ 1.5 × uln * 9. women of reproductive age must use effective contraception during the study period, after the last dose, and for at least 6 months following chemotherapy. it is recommended to start using contraception at least 3 months before the administration of the investigational drug; unsterilized males must also be required to use effective contraception for at least 6 months during the study period, after the last dose, and following chemotherapy. it is recommended to start using contraception at least 3 months before the administration of the investigational drug. * 10. pd-l1 combined positive score ( cps) \<5 exclusion criteria: * 1. prior treatment with anlotinib hydrochloride or any immune checkpoint inhibitors (anti-pd-1, anti-pd-l1, or anti-ctla-4 antibodies); * 2. history of immunodeficiency disorders, including hiv infection, other acquired or congenital immunodeficiency diseases, or prior organ transplantation; * 3. active hepatitis b or c infection, or active pulmonary tuberculosis; * 4. ct-confirmed ulcerative lesions or fecal occult blood positivity; * 5. history of clinically significant bleeding (excluding epistaxis) within 1 month prior to enrollment; * 6. previous allogeneic bone marrow or solid organ transplantation; * 7. interstitial lung disease including idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or ct-confirmed active pneumonia; * 8. administration of live attenuated vaccines within 4 weeks before study initiation or anticipated during the study through 5 months post-treatment; * 9. systemic corticosteroids (\>10 mg/day prednisone equivalent) or immunosuppressive therapy within 2 weeks prior to study initiation (inhaled or topical corticosteroids are permitted); * 10. known symptomatic cns metastases or leptomeningeal carcinomatosis. patients with previously treated cns metastases may be eligible if neurologically stable for ≥4 weeks without steroids or anticonvulsants; * 11. conditions impairing oral drug absorption (e.g., dysphagia, chronic diarrhea, or intestinal obstruction); * 12. grade ≥2 peripheral neuropathy per nci ctcae v5.0; * 13. active infections requiring systemic antibiotics within 14 days prior to study entry; * 14. hepatic tumor burden exceeding 50% of total liver volume; * 15. bone metastases with impending spinal cord compression risk; * 16. uncontrolled comorbidities including: * poorly controlled hypertension (sbp ≥150 mmhg or dbp ≥100 mmhg despite antihypertensives) * grade ≥2 myocardial ischemia, myocardial infarction, or arrhythmias (qtc ≥480 ms) * nyha class iii-iv heart failure or lvef \<50% by echocardiography * uncontrolled active infections * decompensated liver cirrhosis or active hepatitis * uncontrolled diabetes (fbg \>10 mmol/l) * proteinuria ≥++ on dipstick or confirmed 24-hour urinary protein \>1.0 g * 17. non-healing wounds or fractures; * 18. coagulopathy (inr \>1.5 or aptt \>1.5×uln), bleeding diathesis, or requiring therapeutic anticoagulation: * known bleeding disorders (hemophilia, coagulopathies) or thrombocytopenia * hemoptysis (\>2.5 ml/day) within 2 months * clinically significant bleeding within 3 months (gi bleeding, hemorrhagic ulcers, etc.) * chronic anticoagulation (warfarin/heparin) or antiplatelet therapy (aspirin ≥300 mg/day or clopidogrel ≥75 mg/day) * 19. major surgical procedures within 4 weeks prior to study or anticipated during treatment; * 20. history within 6 months of: * gi perforation/fistula * arterial/venous thromboembolism (excluding stable cerebral infarcts) * 21. clinically significant pleural/peritoneal effusions requiring intervention (asymptomatic minimal effusions not requiring treatment may be permitted); * 22. severe malnutrition; * 23. active substance abuse or psychiatric disorders impairing compliance; * 24. other active malignancies except: * curatively treated malignancies with \>2 year disease-free interval * adequately treated non-melanoma skin cancer or lentigo maligna * carcinoma in situ with complete resection * 25. pregnancy or lactation; * 26. any condition deemed by investigators to compromise patient safety or study integrity; * 27. participation in other clinical trials within 30 days prior to enrollment or planned during study period.